Chronic obstructive pulmonary disease (COPD) has become the third most common cause of death in the U.S., and the number of COPD-associated deaths has doubled over the past 20 years. Age, environmental, and genetic factors affect COPD development and progression. While studies of COPD have evaluated different aspects of lung physiology, pathology, and function very little in vivo information exists on the structure and the role of the acinar airways, even though these airways represent 95% of the lung volume and function as the major gas-exchanging unit. This proposal has an overarching goal of developing a new understanding of the effects of aging, cigarette smoking, and COPD on the lung, by measuring and differentiating all aspects of the structural changes in acinar airways among these conditions. We also aim to understand the interplay between disease of small conducting airways and changes in the structure of acinar airways in regions of gas trapping which are thought to be early events leading to emphysema. Building on our prior discovery of anisotropic 3He gas diffusion in acinar airways, we developed and validated the innovative imaging technique of lung morphometry with hyperpolarized 3He magnetic resonance imaging (MRI) that provides unique in vivo quantitative information on the structure and spatial distribution of acinar airways for this study. We will combine 3He morphometric data with quantitative CT data to obtain unique information on parenchymal (alveolar walls including capillaries) and non-parenchymal (non-capillary vessels, etc.) lung tissue, as well as on disease of small conducting airways. Our Specific Aims focus on establishing quantitative relationships between structural alterations in acinar and small airways and declines in lung function: Aim 1: Identify and compare structural mechanisms of the progressive deterioration in lung function associated with aging in healthy never-smokers and healthy smokers, and differentiate contributions of acinar and small airway disease, by using quantitative metrics determined by MRI-based in vivo lung morphometry and quantitative CT. Aim 2: Identify the structural mechanisms of the progressive deterioration in lung function associated with smoking-related COPD, and differentiate the mechanisms of age-related structural changes in the acinar and small airways (in healthy never-smokers and healthy smokers) from those due to COPD, by using quantitative metrics determined by MRI-based in vivo lung morphometry and quantitative CT. We expect to develop a new approach for assessing the effects of aging and COPD on lung structure and function, provide a new understanding of how aging, cigarette smoking, and emphysema cause lung acinar structural changes and associated deterioration in lung function, and propose novel targets for preventing and treating the major public health problem of COPD.